
The Edwards lab has identified three entirely distinct families of proteins that transport classical neurotransmitters into synaptic vesicles. In the course of this work, they identified the System N and A transporters that participate in the glutamine-glutamate cycle which replenishes synaptically released glutamate. They also contributed to identification of the first opiate receptor and the SV2 family of putative transporters. Originally focused on identification and biological role of vesicular neurotransmitter transporters, the scope of their work has now expanded to include the biophysical mechanisms of neurotransmitter transport, factors that regulate expression of the proton electrochemical driving force, and the recycling of synaptic vesicles studied by live imaging of cultured neurons as well as electrophysiology. Recent work has also extended to the packaging of proteins as well as classical transmitters for regulated release. The analysis extends from basic molecular mechanism to synaptic physiology and behavior, using genetically manipulated mice. The goal of our work is to understand how the properties of neurotransmitter release influence synaptic transmission, behavior, development and neuropsychiatric disease.
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The Membrane Interactions of Synuclein: Physiology and Pathology. Annu Rev Pathol. 2021 Jan 24; 16:465-485. Runwal G, Edwards RH. PMID: 33497259.
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Ion transport and regulation in a synaptic vesicle glutamate transporter. Science. 2020 05 22; 368(6493):893-897. Li F, Eriksen J, Finer-Moore J, Chang R, Nguyen P, Bowen A, Myasnikov A, Yu Z, Bulkley D, Cheng Y, Edwards RH, Stroud RM. PMID: 32439795.
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The mechanism and regulation of vesicular glutamate transport: Coordination with the synaptic vesicle cycle. Biochim Biophys Acta Biomembr. 2020 12 01; 1862(12):183259. Eriksen J, Li F, Edwards RH. PMID: 32147354.
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Structures suggest a mechanism for energy coupling by a family of organic anion transporters. PLoS Biol. 2019 05; 17(5):e3000260. Leano JB, Batarni S, Eriksen J, Juge N, Pak JE, Kimura-Someya T, Robles-Colmenares Y, Moriyama Y, Stroud RM, Edwards RH. PMID: 31083648.
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Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties. Neuron. 2019 05 22; 102(4):786-800.e5. Silm K, Yang J, Marcott PF, Asensio CS, Eriksen J, Guthrie DA, Newman AH, Ford CP, Edwards RH. PMID: 31003725.
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The dual role of chloride in synaptic vesicle glutamate transport. Elife. 2018 07 24; 7. Chang R, Eriksen J, Edwards RH. PMID: 30040066.
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A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry. Nat Commun. 2018 01 23; 9(1):330. Ullman JC, Yang J, Sullivan M, Bendor J, Levy J, Pham E, Silm K, Seifikar H, Sohal VS, Nicoll RA, Edwards RH. PMID: 29362376.
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Loss of a-Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons. eNeuro. 2017 Mar-Apr; 4(2). Pathak D, Berthet A, Bendor JT, Yu K, Sellnow RC, Orr AL, Nguyen MK, Edwards RH, Manfredsson FP, Nakamura K. PMID: 28462393.
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a-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci. 2017 May; 20(5):681-689. Logan T, Bendor J, Toupin C, Thorn K, Edwards RH. PMID: 28288128.
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Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons. Front Synaptic Neurosci. 2017; 9:5. Maas JW, Yang J, Edwards RH. PMID: 28280464.View in: PubMed Mentions:
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One Cycle Fuels Another: The Energetics of Neurotransmitter Release. Neuron. 2017 Feb 08; 93(3):470-472. Silm K, Edwards RH. PMID: 28182901.
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A slow excitatory postsynaptic current mediated by a novel metabotropic glutamate receptor in CA1 pyramidal neurons. Neuropharmacology. 2017 03 15; 115:4-9. Sheng N, Yang J, Silm K, Edwards RH, Nicoll RA. PMID: 27567940.
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Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron. 2016 06 15; 90(6):1189-1202. Mende M, Fletcher EV, Belluardo JL, Pierce JP, Bommareddy PK, Weinrich JA, Kabir ZD, Schierberl KC, Pagiazitis JG, Mendelsohn AI, Francesconi A, Edwards RH, Milner TA, Rajadhyaksha AM, van Roessel PJ, Mentis GZ, Kaltschmidt JA. PMID: 27263971.
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Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism. Neuron. 2016 05 18; 90(4):768-80. Eriksen J, Chang R, McGregor M, Silm K, Suzuki T, Edwards RH. PMID: 27133463.
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Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. Mol Metab. 2015 Nov; 4(11):857-66. Cheung CC, Krause WC, Edwards RH, Yang CF, Shah NM, Hnasko TS, Ingraham HA. PMID: 26629409.
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The role of mitochondrially derived ATP in synaptic vesicle recycling. J Biol Chem. 2015 Sep 11; 290(37):22325-36. Pathak D, Shields LY, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, Kim H, Brand MD, Edwards RH, Nakamura K. PMID: 26126824.
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Mobile binding sites regulate glutamate clearance. Nat Neurosci. 2015 Feb; 18(2):166-8. Edwards RH. PMID: 25622571.
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Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neurosci. 2014 Oct 22; 34(43):14304-17. Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, Ahmad J, Edwards RH, Sesaki H, Huang EJ, Nakamura K. PMID: 25339743.
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Efficient, complete deletion of synaptic proteins using CRISPR. Neuron. 2014 Sep 03; 83(5):1051-7. Incontro S, Asensio CS, Edwards RH, Nicoll RA. PMID: 25155957.
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Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway. Dev Cell. 2013 Nov 25; 27(4):425-37. Asensio CS, Sirkis DW, Maas JW, Egami K, To TL, Brodsky FM, Shu X, Cheng Y, Edwards RH. PMID: 24210660.
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Widespread dysregulation of peptide hormone release in mice lacking adaptor protein AP-3. PLoS Genet. 2013; 9(9):e1003812. Sirkis DW, Edwards RH, Asensio CS. PMID: 24086151.
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The function of a-synuclein. Neuron. 2013 Sep 18; 79(6):1044-66. Bendor JT, Logan TP, Edwards RH. PMID: 24050397.
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Multiple dileucine-like motifs direct VGLUT1 trafficking. J Neurosci. 2013 Jun 26; 33(26):10647-60. Foss SM, Li H, Santos MS, Edwards RH, Voglmaier SM. PMID: 23804088.
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Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J Neurosci. 2012 Oct 24; 32(43):15076-85. Hnasko TS, Hjelmstad GO, Fields HL, Edwards RH. PMID: 23100428.
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Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron. 2012 Jul 26; 75(2):283-93. Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, Edwards RH, Lustig LR. PMID: 22841313.
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AMP-activated kinase links serotonergic signaling to glutamate release for regulation of feeding behavior in C. elegans. Cell Metab. 2012 Jul 03; 16(1):113-21. Cunningham KA, Hua Z, Srinivasan S, Liu J, Lee BH, Edwards RH, Ashrafi K. PMID: 22768843.
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Fabs enable single particle cryoEM studies of small proteins. Structure. 2012 Apr 04; 20(4):582-92. Wu S, Avila-Sakar A, Kim J, Booth DS, Greenberg CH, Rossi A, Liao M, Li X, Alian A, Griner SL, Juge N, Yu Y, Mergel CM, Chaparro-Riggers J, Strop P, Tampé R, Edwards RH, Stroud RM, Craik CS, Cheng Y. PMID: 22483106.
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Vesicular and plasma membrane transporters for neurotransmitters. Cold Spring Harb Perspect Biol. 2012 Feb 01; 4(2). Blakely RD, Edwards RH. PMID: 22199021.
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Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia. J Clin Invest. 2012 Feb; 122(2):507-18. Lee HY, Nakayama J, Xu Y, Fan X, Karouani M, Shen Y, Pothos EN, Hess EJ, Fu YH, Edwards RH, Ptácek LJ. PMID: 22214848.
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Neurotransmitter corelease: mechanism and physiological role. Annu Rev Physiol. 2012; 74:225-43. Hnasko TS, Edwards RH. PMID: 22054239.
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Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport. Nat Neurosci. 2011 Aug 28; 14(10):1285-92. Goh GY, Huang H, Ullman J, Borre L, Hnasko TS, Trussell LO, Edwards RH. PMID: 21874016.
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v-SNARE composition distinguishes synaptic vesicle pools. Neuron. 2011 Aug 11; 71(3):474-87. Hua Z, Leal-Ortiz S, Foss SM, Waites CL, Garner CC, Voglmaier SM, Edwards RH. PMID: 21835344.
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Pathway-specific genetic attenuation of glutamate release alters select features of competition-based visual circuit refinement. Neuron. 2011 Jul 28; 71(2):235-42. Koch SM, Dela Cruz CG, Hnasko TS, Edwards RH, Huberman AD, Ullian EM. PMID: 21791283.
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Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem. 2011 Jun 10; 286(23):20710-26. Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH. PMID: 21489994.
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RNAi screen identifies a role for adaptor protein AP-3 in sorting to the regulated secretory pathway. J Cell Biol. 2010 Dec 13; 191(6):1173-87. Asensio CS, Sirkis DW, Edwards RH. PMID: 21149569.
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Metabolic control of vesicular glutamate transport and release. Neuron. 2010 Oct 06; 68(1):99-112. Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, Uneyama H, Edwards RH, Nicoll RA, Moriyama Y. PMID: 20920794.
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Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci. 2010 Jun 16; 30(24):8229-33. Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A. PMID: 20554874.
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Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways. J Neurosci. 2010 Jun 09; 30(23):7917-27. Onoa B, Li H, Gagnon-Bartsch JA, Elias LA, Edwards RH. PMID: 20534840.
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Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron. 2010 Mar 11; 65(5):643-56. Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, Rayport S, Edwards RH. PMID: 20223200.
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Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci. 2010 Feb; 13(2):232-8. Noh J, Seal RP, Garver JA, Edwards RH, Kandler K. PMID: 20081852.
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Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010 Jan 14; 65(1):66-79. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. PMID: 20152114.
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Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature. 2009 Dec 03; 462(7273):651-5. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. PMID: 19915548.
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Synaptic and extrasynaptic factors governing glutamatergic retinal waves. Neuron. 2009 Apr 30; 62(2):230-41. Blankenship AG, Ford KJ, Johnson J, Seal RP, Edwards RH, Copenhagen DR, Feller MB. PMID: 19409268.
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Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron. 2009 Apr 30; 62(2):218-29. Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, Krantz DE, Kobayashi K, Edwards RH, Sulzer D. PMID: 19409267.
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What the neuron tells glia. Neuron. 2009 Mar 26; 61(6):811-2. Edwards R. PMID: 19323989.
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Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. J Neurosci. 2008 Nov 19; 28(47):12305-17. Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH. PMID: 19020024.
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Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron. 2008 Jan 24; 57(2):263-75. Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH. PMID: 18215623.
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Pharmacology of neurotransmitter transport into secretory vesicles. Handb Exp Pharmacol. 2008; (184):77-106. Chaudhry FA, Boulland JL, Jenstad M, Bredahl MK, Edwards RH. PMID: 18064412.
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Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances. Annu Rev Pharmacol Toxicol. 2008; 48:277-301. Chaudhry FA, Edwards RH, Fonnum F. PMID: 17883368.
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The neurotransmitter cycle and quantal size. Neuron. 2007 Sep 20; 55(6):835-58. Edwards RH. PMID: 17880890.
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Physiology versus pathology in Parkinson's disease. Proc Natl Acad Sci U S A. 2007 Jul 17; 104(29):11867-8. Nakamura K, Edwards RH. PMID: 17623781.
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Vesicular glutamate transporter 1 is required for photoreceptor synaptic signaling but not for intrinsic visual functions. J Neurosci. 2007 Jul 04; 27(27):7245-55. Johnson J, Fremeau RT, Duncan JL, RenterÃa RC, Yang H, Hua Z, Liu X, LaVail MM, Edwards RH, Copenhagen DR. PMID: 17611277.
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Thyronamines inhibit plasma membrane and vesicular monoamine transport. ACS Chem Biol. 2007 Jun 15; 2(6):390-8. Snead AN, Santos MS, Seal RP, Miyakawa M, Edwards RH, Scanlan TS. PMID: 17530732.View in: PubMed Mentions:
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Do different endocytic pathways make different synaptic vesicles? Curr Opin Neurobiol. 2007 Jun; 17(3):374-80. Voglmaier SM, Edwards RH. PMID: 17449236.
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Synaptic vesicles: half full or half empty? Neuron. 2006 Sep 07; 51(5):523-4. Hnasko TS, Edwards RH. PMID: 16950150.
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Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron. 2006 Jul 06; 51(1):71-84. Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH. PMID: 16815333.
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PharmGKB submission update: VI. PMT submissions of genetic variations in neurotransmitter transporters (SLC6, SLC17, and SLC18) to the PharmGKB network. Pharmacol Rev. 2006 Mar; 58(1):5-6. Badagnani I, Sorani M, Edwards RH, Brown C, Castro RA, Huang CC, Stryke D, Kawamoto M, Johns SJ, Carlson EJ, Taylor T, Chan W, De La Cruz M, Ferrin TE, Burchard EG, Herskowitz I, Kroetz DL, Giacomini KM. PMID: 16507879.
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Functional implications of neurotransmitter co-release: glutamate and GABA share the load. Curr Opin Pharmacol. 2006 Feb; 6(1):114-9. Seal RP, Edwards RH. PMID: 16359920.
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Sorting of vesicular monoamine transporter 2 to the regulated secretory pathway confers the somatodendritic exocytosis of monoamines. Neuron. 2005 Nov 23; 48(4):619-33. Li H, Waites CL, Staal RG, Dobryy Y, Park J, Sulzer DL, Edwards RH. PMID: 16301178.
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Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci. 2005 Nov 23; 25(47):10913-21. Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH. PMID: 16306404.
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A combinatorial code for the interaction of alpha-synuclein with membranes. J Biol Chem. 2005 Sep 09; 280(36):31664-72. Kubo S, Nemani VM, Chalkley RJ, Anthony MD, Hattori N, Mizuno Y, Edwards RH, Fortin DL. PMID: 16020543.
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Antidepressants and the monoamine masquerade. Neuron. 2005 Apr 07; 46(1):1-2. Sulzer D, Edwards RH. PMID: 15820686.
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Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters. J Comp Neurol. 2004 Dec 13; 480(3):264-80. Boulland JL, Qureshi T, Seal RP, Rafiki A, Gundersen V, Bergersen LH, Fremeau RT, Edwards RH, Storm-Mathisen J, Chaudhry FA. PMID: 15515175.
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Vesicular glutamate transporter 3 expression identifies glutamatergic amacrine cells in the rodent retina. J Comp Neurol. 2004 Sep 27; 477(4):386-98. Johnson J, Sherry DM, Liu X, Fremeau RT, Seal RP, Edwards RH, Copenhagen DR. PMID: 15329888.
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The effect of rare human sequence variants on the function of vesicular monoamine transporter 2. Pharmacogenetics. 2004 Sep; 14(9):587-94. Burman J, Tran CH, Glatt C, Freimer NB, Edwards RH. PMID: 15475732.
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Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 2004 Jul 28; 24(30):6715-23. Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. PMID: 15282274.
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Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science. 2004 Jun 18; 304(5678):1815-9. Fremeau RT, Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J, Chaudhry FA, Nicoll RA, Edwards RH. PMID: 15118123.
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VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 2004 Feb; 27(2):98-103. Fremeau RT, Voglmaier S, Seal RP, Edwards RH. PMID: 15102489.
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The H+-coupled electrogenic lysosomal amino acid transporter LYAAT1 localizes to the axon and plasma membrane of hippocampal neurons. J Neurosci. 2003 Feb 15; 23(4):1265-75. Wreden CC, Johnson J, Tran C, Seal RP, Copenhagen DR, Reimer RJ, Edwards RH. PMID: 12598615.
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Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate. J Neurosci. 2003 Jan 15; 23(2):518-29. Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR. PMID: 12533612.
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The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc Natl Acad Sci U S A. 2002 Oct 29; 99(22):14488-93. Fremeau RT, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer D, Copenhagen DR, Storm-Mathisen J, Reimer RJ, Chaudhry FA, Edwards RH. PMID: 12388773.
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The glutamine commute: take the N line and transfer to the A. J Cell Biol. 2002 Apr 29; 157(3):349-55. Chaudhry FA, Reimer RJ, Edwards RH. PMID: 11980913.
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Glutamine uptake by neurons: interaction of protons with system a transporters. J Neurosci. 2002 Jan 01; 22(1):62-72. Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH. PMID: 11756489.
Robert Edwards attended Yale College and Johns Hopkins Medical School. After clinical training in neurology, he studied the role of nerve growth factor in development as a postdoctoral fellow in William Rutter’s laboratory at UCSF. He then joined the faculty at UCLA in the Departments of Neurology and Biological Chemistry, returning to UCSF in 1995 where he is now the Cahill Professor of Neurology and Physiology.